The goal of chemotherapy of mycobacterial infections is to stop the worsening of the disease, to convert secretions to a noninfectious state by killing the bacilli if possible, and to allow healing of gross pathological damage. Antimycobacterial agents are discussed at length in Medicinal Chemistry, Part I, Alfred Burger, ed. (Wiley-Interscience, N.Y. 1970), Chapter 19.
Pyrazinamide is known for the therapy of tuberculosis. The synthesis of pyrazinamide was described by Kushner et al, J. Am. Chem. Soc. 74:3617 (1952), and the compound was patented in 1954 as a tuberculostatic agent. Williams, U.S. Pat. No. 2,677,641. When pyrazinamide is used alone resistance develops quickly, and for this reason it is usually administered in combination with other drugs such as isoniazid. Another disadvantage of pyrazinamide is its hepatotoxicity.
Pyrazinamide is only active against Mycobacterium (M.) tuberculosis. It is not active against the closely related organism M. bovis or other mycobacteria. In particular, it has been reported to be inactive against M. avium [Heifets et al. Am. Rev.. Resp. Dis. 134:1287-1288 (1986)] which has become a serious cause of disseminated infection among patients with AIDS.
Other than our own earlier patent, (U.S. Pat. No. 4,962,111), there is little or no support in the art for using pyrazinoic acid esters as tuberculostatic agents. U.S. Pat. No. 2,646,431 issued to Dalalian and Kushner covered pyrazine derivatives and methods of preparation. One such group of derivatives, thiolpyrazinoates, showed bacteriostatic and bacteriocidal properties against human tubercle bacillus. However, the specification states that in general, pyrazine monocarboxylic acid and derivatives such as esters do not possess bacteriostatic or bacteriocidal properties.
In 1954 Kushner et al. [J. Am. Chem. Soc. 77:1152-1155] reported the use of ethyl mercaptan and related compounds in experimental treatment of tuberculosis. Isopropyl thiopyrazinoate applied subcutaneously exhibited activity in a standardized mouse test. However, the authors attributed this activity to the release of ethyl mercaptan, not to the pyrazinoyl residue. Brown et al. [J. Am. Chem. Soc. 76:3860 (1954)] also reported that ethyl mercapto compounds had antituberculosis activity, thus supporting the Kushner et al. assertion that the activity of ethyl thiopyrazinoate was due to ethyl mercaptan and not the pyrazinoyl residue. The only suggestion that pyrazinoic acid esters might have some value in tuberculosis therapy is found in Solomons and Spoerri, [J. Am. Chem. Soc. 75:679 (1953)]. In the course of evaluating esters of pyrazinoic and pyrazine-2,3-dicarboxylic acids as local anesthetics, the authors learned of the effectiveness of pyrazinamide as a tuberculostatic agent. The authors tested their anaesthetic compounds for in vitro activity against Myobacterium tuberculosis H37RV and reported that a few were active, including N,N-dimethyl-2-aminoethyl pyrazinoate. No further work appears to have been done with this compound, and its effectiveness against other mycobacteria, including pyrazinamide-resistant M. tuberculosis, would not have been obvious on the basis of this isolated in vitro test.
In 1958, Suzuki et al. [Takamine Kenkyusho Nempo 10:19-23] reported that the pyrazinoate ester of chloramphenicol was inactive against a number of bacteria including M. tuberculosis.
It has now been surprisingly found that esters of pyrazinoic acid are active against the clinically important Mycobacterium avium complex. In exploring the breadth of operable esters, which appears to include all ester residues that can be cleaved to pyrazinoic acid by the target bacterium, many esters have been prepared within a novel genus of chemical compounds.